What is Von Willebrand Disease?

What is Von Willebrand Disease?
Von Willebrand Disease (VWD) is the most common bleeding disorder that people have. In fact, it is not a single disease, but a family of related diseases. All the different types are caused by a problem with the Von Willebrand Factor (VWF). This is a protein in blood, which is necessary for proper blood coagulation, or clotting. The genes that make VWF are " turned on " in two cell types in the body:
• the lining cells of blood vessels (endothelial cells) and
• platelets.
When there is not enough VWF in the blood, or when it does not work the way it should, the blood takes longer to clot.

How does blood clot normally?
Blood is carried throughout the body within a network of blood vessels. When tissues are injured, damage to a blood vessel may result in leakage of blood through holes in the vessel wall. The vessels can break near the surface, as in a cut. Or they can break deep inside the body, making a bruise or an internal hemorrhage.
Platelets are small cells circulating in the blood. Each platelet is less than 1/10,000 of a centimetre in diameter. There are 150 to 400 billion platelets in a normal litre of blood. The platelets play an important role in stopping bleeding and beginning the repair of injured blood vessels.
When a blood vessel is damaged, there are four stages in the normal formation of a clot.
Stage 1: The blood vessel is damaged and the bleeding starts.
Stage 2: The blood vessels constrict to slow the flow of blood to the injured area.
Stage 3: Platelets stick to, and spread on, the walls of damaged blood vessels. This is called platelet adhesion. These spreading platelets release substances that activate other nearby platelets which then clump together at the site of injury to form a platelet plug. This is called platelet aggregation.
Stage 4: The surface of these activated platelets then provides a surface on which blood clotting can occur. Clotting proteins circulating in the blood are activated on the surface of the platelets to form a mesh-like fibrin clot.
These proteins (Factors I, II, V, VII, VIII, IX, X, XI, XII AND XIII and Von Willebrand Factor) work like dominos, in a chain reaction. This is called the coagulation cascade.

How does a person get Von Willebrand Disease?
Von Willebrand Disease is an hereditary disorder. It is caused by an abnormal gene.
Each cell of the body contains structures called chromosomes. A chromosome is a long chain of chemicals known as DNA. This DNA is arranged into hundreds of units called genes which determine such things as the colour of a person's eyes.
Each cell contains 46 of these chromosomes arranged in 23 pairs. Von Willebrand Disease is caused by a defect on chromosome 12. The defect could be on the chromosome 12 from the mother, on the chromosome 12 from the father, or on both.
There are two ways of getting VWD :
• It can be passed from a parent who is a carrier to a child at the time of birth.
• One of the baby's genes can undergo a change. This is called a genetic mutation. The baby's parents are normal.
Male and female children have an equal chance of inheriting VWD. Because it is an hereditary disorder, VWD often affects several members of the same family. One can often trace VWD through a family tree.

Is there always a history of bleeding in the family?
Not always. There are several reasons why.
The level of VWF is not the same from person to person even in the same family. As a result, one person may bleed more than another.
Blood type can play a role. People with Type O blood often have lower levels of VWF than people with Types A, B and AB. So people with Type O blood may have more problems with bleeding.
Doctors believe there are other factors that also affect how severe symptoms are, but they are not yet well-known.
There may be no history of the disease because no one in the family has it. The baby could have gotten the abnormal gene through a new mutation. In this case, chromosome 12 changes at conception or soon after. That baby's parents are normal. However, the baby, after growing up, could the pass on VWD to its children.

How does VWD affect the normal clotting of blood?
Von Willebrand Disease affects the last two stages in the blood clotting process.
In Stage 3, a person may not have enough VWF in the blood, or it may not work normally. Because of this, the VWF cannot act as a glue to hold the platelets in place at the site of the damage to the blood vessel. The platelets do not stick to the lining of the vessel.
In Stage 4, the VWF carries Factor 8 (written Factor VIII) in the bloodstream. Factor VIII is one of the proteins needed to make a solid clot. When the VWF is present at low levels, so is Factor VIII. Without normal levels of Factor VIII, a solid clot takes a very long time to form.

How common is VWD?
Doctors now think that VWD could affect as many as 1 in 100 people. Because many of these people have only very mild symptoms, only a small number of them know they have the disease.

Who is affected by VWD?
Von Willebrand Disease affects both men and women. However, because many women with VWD have heavy menstrual bleeding and prolonged bleeding after childbirth, more women have symptoms than men.
Children, too, can have VWD. They are born with it. This is because VWD is an hereditary disorder.

Can VWD be passed from parents to children?
Yes. If one or both of the parents have VWD, they can pass it on to their children.

How serious is VWD?
It depends on the type of disease. Fortunately, there are effective treatments for all types of VWD. What's more, some researchers are finding that " ... mild VWD could be a health benefit. " They explain it this way. VWD makes it more difficult for platelets to stick together. Because of this, people with VWD could have less chance of blood clots blocking arteries (atherosclerosis), and therefore, less chance of heart attacks and strokes.

What are the different types of VWD?
Von Willebrand Disease is divided into three categories - Type 1, Type 2 and Type 3.
Type 2 VWD is itself divided into several sub-types.

What is Type 1 VWD?
Type 1 VWD is the most common form, affecting 75% of all people with VWD. In Type 1 VWD, the Von Willebrand Factor (VWF) works normally, but there is not enough of it.
Many people have no symptoms of VWD at all until a bad injury or an operation. Then, they could have serious bleeding.
Others have mild symptoms such as:
• bleeding from their gums
• minor bruises
• prolonged bleeding from cuts.
Some women with Type 1 VWD have heavy, prolonged bleeding during their periods, called menorrhagia. This can have a big effect on health and quality of life.
Injuries and surgery can lead to severe bleeding even in this mild form of VWD. That's why it's important for people who think they might have VWD to get tested.

What is Type 2 VWD?
Type 2 VWD is much less common than Type 1. It represents 20-25% of all cases.
In Type 2 VWD the amount of VWF in people's blood is often normal. The problem is that the VWF does not work properly. There are several sub-types of Type 2 VWD. It is important to get an exact diagnosis because the sub-types can be treated differently.

What is Type 3 VWD?
Type 3 VWD is very rare. It affects about 1 in 500,000 people. However, it is the most severe type of VWD. People with Type 3 VWD have very little VWF in their blood. Because VWF transports Factor VIII, they also have very low levels of Factor VIII. As a result, bleeding happens often and, if untreated, can be serious.
In order for a child to get Type 3 VWD, both parents must be carriers of the defective VWD gene.

Do the parents of a child with Type 3 VWD show signs of the disease?
In most cases both parents of a child with severe Type 3 VWD are carriers. However, they may or may not have symptoms themselves.

What are the symptoms of Von Willebrand Disease?
Common symptoms of VWD are:
• frequent nose bleeds
• easy bruising
• bleeding from the gums when baby teeth fall out or after tooth extractions
• heavy bleeding during menstruation (menorrhagia)
• menstrual bleeding that lasts longer than 7 days.
• bleeding into the stomach or intestine (gut).
However, many people with VWD do not notice anything is wrong. They realize they have a bleeding problem only when:
• another person in the family is diagnosed with VWD or
• they have a serious injury or surgery.

Can women with VWD have children?
Yes. For most women with VWD, pregnancy is not a problem. Miraculously, the level of VWF in the blood goes up during pregnancy and at the moment of childbirth. However, after childbirth, VWF levels fall quickly, and bleeding can continue for many weeks.

Are symptoms of VWD the same for everybody?
No. The symptoms of VWD vary greatly from person to person. Even members of the same family will have different symptoms.
The type of VWD affects the severity of the symptoms, too.
• Type 1 VWD and Type 2 VWD are usually very mild.
• Type 3 VWD is severe. People have bleeding into muscles and joints, often for no reason.
Is diagnosing Von Willebrand Disease simple?
No, diagnosing VWD is not simple. Many doctors are not familiar with it. Some people live with VWD for many years before they find out what it is.
In the past VWD has often been misdiagnosed. For example:
• a person with a low platelet count because of Type 2 VWD could be diagnosed with leukemia
• a woman with heavy, prolonged menstrual bleeding because of VWD, who has not responded to hormone therapy, could be advised to have a hysterectomy.
A person who thinks he/she has a bleeding problem should see a hematologist who specializes in bleeding disorders at a Hemophilia /Bleeding Disorder Treatment Centre.

What tests will be done to diagnose Von Willebrand Disease?
A doctor who suspects VWD will first take a complete family history. He/she will then do a number of blood tests to find out:
• if the person has VWD and
• what type of VWD the person has.

The tests are ...

Bleeding time This measures the length of time it takes for a simple cut to stop bleeding.

Factor VIII:C This measures the amount of Factor VIII clotting activity.

VWF: antigen This measures the amount of Von Willebrand Factor.

Ristocetin cofactor activity This measures how well the VWF works.

VWF multimers This measures the structure of the VWF.

Platelet function tests These measure how well the platelets work.

How long does it take to get the results?
Some of the tests must be done in a specialized laboratory. Therefore, it may be 2 or 3 weeks before test results come back.
Sometimes tests need to be repeated. This is because a person's test results can be normal one day and abnormal a month later. There are a number of things that cause the level of VWF to rise in the blood. Some of them are:
• being pregnant
• having an infection
• doing a lot of exercise
• being on the Pill (oral contraceptives).
Is medical treatment always necessary for bleeds?
No. Minor bleeding episodes associated with VWD often do not require medical treatment. For example:
• small bruises usually disappear on their own.
• nose bleeds may be stopped by tilting the head forward and pinching the nostrils together for 10-15 minutes
• bleeding from minor cuts can be stopped by applying pressure.
However, sometimes medical treatment is necessary. The type of treatment depends in part on the type of VWD a person has.

What are the treatments for Type 1 Von Willebrand Disease?
Desmopressin
Desmopressin is a synthetic drug which is a copy of a natural hormone. It acts by releasing VWF stored in the lining of the blood vessels. Desmopressin is not made from blood.
Desmopressin is the treatment of choice for Type 1 VWD.
Desmopressin can be taken in three different ways.
• It can be injected into a vein. Most often, the brand name for this kind of desmopressin is DDAVP.
• It can be injected under the skin. The brand name for this kind of desmopressin is often Octostim.
• It can be taken by nasal spray. The brand name of the nasal spray is often Octostim Spray.
Desmopressin is effective for almost all people with Type 1 VWD. However, different people respond to desmopressin in different ways. Therefore, a doctor needs to do tests to find out each individual's response to the drug. Ideally, these tests are done before any urgent need for the drug, such as surgery.
Since desmopressin acts by releasing VWF stored in the body, you cannot " go to the well " too often. A sufficient amount of time, usually 24 hours, must elapse between doses of desmopressin to allow the body to rebuild its stores.
In major surgery, desmopressin alone may not be enough to control bleeding. In such a case, a person should also receive a concentrate of VWF and Factor VIII. (See next section: Factor VIII Concentrates with Von Willebrand Factor.)
Desmopressin can sometimes have some mild side effects. These are:
• facial flushing
• mild headache
• nausea and abdominal cramps.
Desmopressin is an anti-diuretic, that is, it can make the body retain water. Therefore, doctors recommend that after receiving desmopressin people drink only enough fluid to satisfy thirst.
If a person has a very bad headache or has not been able to pass water 24 hours after taking desmopressin, he / she should go to the Hemophilia / Bleeding Disorder Treatment Centre or emergency room for help.

Cyklokapron and Amicar
Cyklokapron (tranexamic acid) and Amicar (aminocaproic acid) are drugs that help to hold a clot in place once it has formed. They act by stopping the activity of an enzyme, called plasmin, which dissolves blood clots.
They do not help to actually form a clot. This means they can not be used instead of desmopressin or VWF concentrate.
They can be used to hold a clot in place in mucous membranes such as:
• the inside of the mouth
• the inside of the nose
• inside the intestines (the gut)
• inside the uterus (the womb)

Cyklokapron and Amicar have proven very useful for people with VWD. They are used:
• before dental work
• when a person has mouth, nose and minor intestinal bleeding
• for women with heavy, prolonged menstrual bleeding.

These drugs come in tablet form.
Cyklokapron and Amicar can sometimes have some mild side effects. These are:
• feeling sick to the stomach (nausea)
• feeling tired or sleepy
• feeling dizzy
• having loose bowel movements (diarrhoea)
• having pain in the stomach.
These mild side effects go away when:
• a person stops taking the drugs
• the doctor reduces the dosage.

Thrombin
Thrombin is a natural clotting agent that comes in powder form. Bleeds in the mouth or nose can be stopped by applying Thrombin directly to the bleeding site.

History of VWD

In 1925, Dr. Erik von Willebrand of Helsinki published, in Finnish, his astute observations on a large family with a bleeding disorder from one of the Aland islands in the gulf between Sweden and Finland. He described all the clinical symptoms mentioned above. He surmised that inheritance was dominant but that the most severely-affected members of the inbred family were homozygotes. The only clearly abnormal laboratory tests, among the few available laboratory tests, among the few available at the time, were the bleeding time(BT) and a capillary-fragility test. (The latter is performed by inflating a blood-pressure cuff around the upper arm, to a level between systolic and diastolic pressure, for a few minutes and observing the fore-arm for petechiae.) The platelet count was normal arm for peteciae.) The platelet count was normal but there appeared to be minor morphologic changes in the platelets (not subsequently substantiated). The whole blood clotting time (prolonged in hemophilia) was normal. Dr. Von Willebrand concluded that the disorder was due to “a disturbed function of the thrombocytes and a general lesion of the capillary walls “and called it “pseudohemophilia”.